This is a grant renewal for studies on formulations of high molecular weight (MW less than 1000 Daltons) drugs, such as polypeptides. In this proposal, we intend to carry out studies towards understanding (and ultimately rationally improving) the stability of solid peptides and proteins within polymeric delivery systems. Specifically, we propose to examine the relationship between protein solid-state stability and 1) protein structure; and 2) Tg the glass transition temperature; then 3) examine the physical-chemical properties within polymers; and finally 4) apply the knowledge gained from above studies together towards examining stability of proteins loaded within polymeric matrices. We will use a number of model proteins with the goal of developing, for the first time, comprehensive guidelines for predicting and enhancing the stability of proteins under pharmaceutically relevant conditions.